development is critical. Typically, a design
freeze initiates just before the validation/
verification stage of a medical device.

Any changes made to the device design
post design freeze, once initial data has
been submitted for regulatory review,
may trigger additional design output requirements. Ideally, sponsor companies
should think about incorporating clinical studies (including human factors)
prior to implementing the design freeze.

A development pilot study prior to any
pivotal clinical trial can give valuable
insight into product performance. If the
product remains consistent and robust
throughout the studies, the data could
feasibly be used to propel the product
ahead of plan.

Sometimes, pharma companies are
reluctant to change a device once on
the market because that usually results
in additional clinical studies and a
significant amount of money and time
to resubmit. Regulatory delays can be
significant for a combination product
worth several million dollars. Conversely, some device companies seem to
have an affinity for making changes to a
device; they want the next generation,
better ergonomics, with more human
factor studies.

Design freeze is extremely important
because if the design keeps changing
and no stage-gate or control is built into
the process, sponsor companies will find
it difficult knowing what to incorporate
for design reviews, design verification
protocols, and subsequent validation
data. Regulators want to see a firm plan
with traceability from the base level of
design (proof of concept). They also
want to ensure that the device they are
approving is just as safe and effective as
the constituent drug/biologic part, from
a clinical standpoint. Do not be surprised
during the submission process if additional clinical data is requested above what
was already submitted.

5. Use risk-based decision makingto develop and bring the product tomarket. Consider any risk, such as thepotential harm the device could cause tothe patient, when developing a combina-tion product. Use failure modes and effectanalysis to look at any risk in develop-ment for both individual constituent partsand the system as a whole.

For instance, when the drug/biologic
target product profile (TPP) is being
established, the sponsor company can
integrate the device design development
concept into discussion by asking how
a material in the device’s manufacture
could introduce a leachable/extractable
that would pose significant harm or risk
to patient and product stability profile.

Consider a sponsor company working
with a device design and development
company to produce an insulin auto-in-jector. The next–generation auto-injec-tor may require an option to change
the grade or properties of a polymer or
resin additive. Using risk-based decision
making, the two companies need to
work together to determine if they have
to go back and complete biocompatibil-ity studies with the resin change and the
drug to see if they were compatible.

It comes down to determining what
risk strategy the sponsor company will
employ in the development of the combination product, and will the sponsor
company deploy it in separate parts —
one for the drug and one for the device.

Or, is it going to be a combined strategy
where the drug and device companies
are working together in planning the
development?

6. Establish a product stability
strategy. The FDA and EU want to
see stability studies on file before a final
submission is sent to them. Determine
if the device and drug should be studied
with the two components together,
independent of one another, or both.

Analyze how or if the device changes the actual drug once the two are
paired together over the shelf life of the
product. The sponsor company will need
to provide details of these studies and
validation that the products are safe for
patient consumption before the regulatory
bodies will consider approving. You also
need to consider what specific tests need
to be performed on each constituent part
and together as a system. For instance,

if the company is performing shock and
vibration studies on a particular drug delivery device, should they do this separate
from the drug being included, together,
or both? If conducting accelerated aging
on a system or constituent products, is
the company carrying out physical testing
and then monitoring all relevant time
points? Is stability ending at the end of
shelf life only, or does the company go
past expiry? All are factors that should be
included in a sound stability strategy.

Concluding Advice

The regulatory submission and approval
process for combination and drug
delivery devices is still evolving; sponsor
companies may have unanswered
questions. Implementing some of the
essential guidelines above are key to improving the odds of first-time regulatory
approval. Many companies file with not
enough or the wrong information, or
don’t establish an appropriate QMS, all
of which slows approval process and
costs more time and money. Speed to
market is then lost. More meaningful
data that validates the product as a
system,and more sound and holistic
product development and cGMP processes, increase chances are of first-time
approval ultimately saving the sponsor
company both time and money. MDT